WO1989006232A1

WO1989006232A1 - Butadiene compounds and their medicinal use

Info

Publication number: WO1989006232A1
Application number: PCT/JP1988/001343
Authority: WO
Inventors: Mitsuhiro Konishi; Hiroshi Tanaka; Michio Terasawa; Hiroshi Ochi
Original assignee: Yoshitomi Pharmaceutical Industries, Ltd.
Priority date: 1987-12-29
Filing date: 1988-12-27
Publication date: 1989-07-13

Abstract

Butadiene compounds represented by general formula (I) (wherein R1 represents hydrogen, lower alkyl, carboxy-lower alkyl, amino-lower alkyl, mono- or di-lower alkylamino-lower alkyl or aralkyl, n R2 groups each represent halogen, lower alkyl, lower alkoxy or hydroxy, R3 represents hydrogen or lower alkyl, Het represents pyridyl, N-lower alkyl-pyridinium, quinolyl, 4-oxo-3H-quinazolyl, and n represents 0 or an integer of 1 to 4, provided that when n represents an integer of 2 to 4, n R2 groups may be the same or different from each other) and their salts are disclosed. The butadiene compounds and their salts possess 5-lipoxygenase inhibiting activity, lipid peroxidation preventing action, leucotriene D4-antagonistic action, activity of inhibiting the release of histamine and SRS-A, etc. and are useful as agents for treating various diseases such as bronchial asthma, allergic diseases (e.g., allergic rhinitis), immunological diseases (e.g., auto-immunodeficiency, infectious diseases, etc.), inflammatory diseases (e.g., articular rheumatism, ankylosing spondylitis, etc.), psoriasis, cerebrovascular disease, ischemic heart disease, thrombosis, etc.

Description

Specification

Butadiene compounds and their pharmaceutical uses

"Technical field"

The present invention relates to a novel butadiene compound useful as a medicament, its pharmacologically acceptable salt, and its medicinal use.

"Background technology"

Chem. Pharm. Bull., Vol. 12 (11), pages 1344 to 1351 (1964), quinazolidinum bromide with Grignard reagent 1— (2—Pyridyl) -14—Phenyl-1,3—butadiene can be obtained as described in Chem. Pharm. Bull., Volume 13 (4), pages 503-510. According to (1965), the ring-opening reaction of monomethyl quinazolyl bromide in phenylmagnesium bromide yields 1 (3-methyl 1-2-viridyl) -4- phenyl-1> 3- Butadiene or 1- (2-viridyl) -2-methyl-4-phenyl-1 1,3-butadiene can be obtained, Chem.

Pharm. Bull., The Vol. 26 (8) 2334 to 2339 page (1978), glyceryl Bologna reagent Nyorubenzo _[a] over Oyobibe emission zone [b] quinolizinium Li Jiniumuburomai de ring opening According to the reaction, it is possible to obtain 2- (4-phenyl-1,3-buta-genyl) quinoline or 1- (4-phenyl-1,3-buta-genyl) isoquinoline. The specification states that 2—cinnamylidene—2—bikolin, that is, 1— (2—biligil) -4-1phenyl-1,3—butadiene, etc., have insecticidal activity. Disclosed, and furthermore, the journal 'ob', Medicinazole ', Chemistry (J. Med. Chem.) Vol. 19 (9) 1079-1088 Page (1978) states that 1— (3— or 4-pyridyl) 1-4— Phenyl (Although it may have dichloro, nitro or phenyl as a substituent) 1-1,3-butadiene is described.

By the way, recently, the metabolic pathway of arachidonic acid and the chemistry of its metabolites have made delicate progress, which has recently been known as the arakidonic acid cascade. It has become clear that saturated fatty acids roycotrienes play an important role in inflammation and allergy.

Locotriens have a strong bronchoconstrictive action and are known to be the same substance as SRS-A (slow reacting substance of anaphylaxis), which induces type I allergic reactions. You.

In addition, roycotrines have a strong vasoconstrictor action, and are known to cause vasospasm, ischemia, hypertension and the like.

Therefore, the appearance of a compound having an activity of inhibiting the action of 5-lipoxygenase has been desired for treating these diseases.

"Disclosure of the invention"

'The inventors of the present invention have conducted various studies to provide a compound having 5-riboxygenase inhibitory activity. As a result, a 1-phenyl-1,3, butadiene compound having an oxy group as a substituent on a funinyl group was obtained. The present inventor has found that it has an excellent inhibitory action and is useful as a medicine, and has completed the present invention.

In other words, the present invention is a general formula I

Het-CH = CH-C = CH- ( ^/ , '>> (I)

, (R ² ) _n

(Formula Φ, R ¹ is hydrogen, lower alkyl, carboxy lower alkyl, amino lower alkyl, mono- or G-lower alkyl, lower alkyl, aryl, n R ² are each halogen lower alkyl, Lower alkoxy, hydroxyl group, R ³ is hydrogen, lower alkyl, Het is pyridyl, N-lower alkylpyridinium, quinolyl, 4-oxo-13H-quinazolyl, n is 0 or 1 Represents an integer of 4 to 4. However, when n represents an integer of 2 to 4, n R ² may be the same or different.

A butadiene compound represented by the formula:

In the above formula (I), examples of the lower alkyl include those having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, and tertiary butyl. , Butoxy, tertiary butoxy, etc., having 1 to 4 carbon atoms, such as chlorine, bromine, fluorine, iodine, and aralkyl. For example, benzyl, 2-phenylethyl, 1-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, and the like in the lower alkenyl of carboxy lower alkyl are the same as the lower alkyl described above, and the carboxy lower alkyl is And carboxymethyl, 2-carboxyethyl, 3-carboxyprovir, 4-carboxybutyl, etc., are among the lower aminoalkyls. That Arukiru part the lower Arukiru same Deari, is the § Mi-lower-Arukiru § Mi Bruno methylation, 2 For example, aminoethyl, 3-aminopropyl, 4-aminobutyl, etc., both lower alkyl groups in mono- or di-lower-alkyl lower aminoalkyl are the same as those in lower alkyl. Mono or G-lower alkylamino is a lower alkyl, methylaminomethyl, 2-methylaminopropyl, 3-methylaminopropyl, 4-methylaminobutyl, Ethylaminomethyl, 2—ethylaminobutyl, 4—ethylaminobutyl, propylaminomethyl, 2—propylaminomethyl, 4—propylaminobutyl, butylaminomethyl, 2—butylaminoethyl, 4-butylaminobutyl, dimethylaminomethyl, 2—dimethylaminopropyl, 3—dimethylaminopropyl, 4dimethyl Cylaminobutyl, tert-aminomethyl, 2—Jethylaminomethyl, 4-Jethylaminobutyl, Diproviraminomethyl, 2 Diproviraminoethyl, 4—Diproviraminobutyl, 2-Dibutylaminomethyl, 2— Dibutylaminoethyl, 4-dibutylaminobutyl and the like. Examples of the lower alkyl moiety in N-loweralkylpyridinium include lower alkyl similar to the above.

The salt of the compound of the general formula (I) of the present invention is a pharmacologically acceptable salt, such as tobacco acid addition salt (hydrochloride, hydrobromide, sulfate, Phosphate, fumarate, maleate, succinate, succinate, P—addition salts with inorganic or organic acids such as toluenesulfonate), metal salts (sodium salt) Salt, potassium salt, calcium salt, aluminum salt, etc.), quaternary ammonium salt, salt with alumina (such as salt with triethylamine), amino Examples include acid addition salts (salts with lysine, glutamine, etc.), and when Het- is N-lower alkylpyridinium, forms salts with halogens.

The compounds of the general formula (I) of the present invention and salts thereof may also exist in the form of hydrates, and the present invention covers such hydrates. The compound of the general formula (I) of the present invention includes cis- and trans-isomeric geometric isomers and mixtures thereof, and the present invention covers them.

According to the present invention, the compound of the general formula (I) can be produced, for example, by the following method.

Method A

-Formula of compound of general formula (I)! ? Compounds in which ¹ is lower aralkyl or aralkyl are represented by the general formula

Het-CH ₂ P ⁺ (~ ^ S) ₃ '-(Π)

[In the formula, X represents a halogen atom (chlorine, bromine, iodine, fluorine), and Het has the same meaning as described above. ]

The Wittig reagent [hereinafter referred to as compound (（) and ぃぅ] represented by the general formula

(In the formula, β ⁴ is lower aralkyl or aralkyl in R ¹ , and other symbols are as defined above.)

Can be obtained by subjecting a compound represented by the following [hereinafter, compound (m) and ぃぅ] to a Wittig reaction. The reaction is usually carried out using a deoxidizing agent such as bistrimethylsilylaminolithium salt, in a solvent inert to the reaction, such as tetrahydrofuran, dimethylfuramide, preferably in a nitrogen stream. Below — progress from 50 'C to room temperature, a few hours from rush to about 24 hours. '' Starting compound (H)

Het-CH ₂ X (IV)

(In the formula, each symbol has the same meaning as described above.)

And triphenylphosphine in a reaction inert solvent such as benzene, toluene, tetrahydrofuran, dimethylformamide, etc. from room temperature to about 150 ° C. The reaction is carried out for about 8 to about 24 hours, and the starting compound (ΠΠha-general formula (V)

(In the formula, each symbol has the same meaning as described above.)

[Hereinafter, compound (V) and compound] represented by the general formula

3 -CH ₂ CH0 (VI)

(In the formula, R ³ has the same meaning as described above.)

Can be obtained by reacting with a compound represented by the formula in an aqueous solution of alkaline (such as sodium hydroxide) at a temperature of about 80 ° C. under ice cooling for 30 minutes to several days.

Method B

The compound obtained by Method A is

Het-CHs (W)

(Equations Φ and He are as defined above.) And the compound (m) can be produced, for example, by refluxing in a large excess of anhydrous acetic acid for 10 to 72 hours.

Method c

Compounds of the formula (I) wherein R ¹ is lower aralkyl or aralkyl and R ³ is a hydrogen atom are represented by the general formula

(In the formula, each symbol has the same meaning as described above.)

A compound represented by the following formula (hereinafter, compound (\ 1) and ぃぅ) and a general formula

Het-CH = CH-CH0 (K)

(In the formula, Het has the same meaning as described above.)

By reacting a compound represented by the following formula [hereinafter, compound (IX) and ぃぅ].

The reaction proceeds under the same conditions as in Method A.

The starting compound () is obtained by reducing the compound (V) with a reducing agent such as sodium borohydride to form an alcohol form, and then forming a chloride form with thionyl chloride or the like. The compound (K) may be reacted with chloroacetaldehyde and triphenylphosphine in chloroform, for example, by reacting with phenylphosphine. The reagent is treated with an aqueous solution of sodium hydroxide in the next step to synthesize the ylide form.

Het-CHO (X) (In the formula, Het has the same meaning as described above.)

Can be obtained by reacting with the compound represented by

Method D

—Of the compounds of the general formula (I), compounds in which Het is N—lower alkylpyridinium are represented by the general formula (XI)

(In the formula, each symbol has the same meaning as described above.)

And a compound represented by the general formula

R ⁵ -Y (X Π)

(Wherein β ⁵ represents a lower alkyl, and Υ represents an anion residue).

The reaction usually proceeds in the absence of a solvent or in a solvent inert to a reaction such as chloroform or butanol at room temperature to 200 ° C. for several hours to several minutes.

Method Ε

Chi U of compounds of chromatography general formula (I), over R ¹ is Aru compound with hydrogen atoms is obtained METHOD A to D Nyori general formula

(In the formula, each symbol has the same meaning as described above.)

In a reaction-inert solvent such as dichloromethane and chloroform in an ice-cooled to room temperature at about 1-10 equivalents of triodor. It may be possible to react with boron iodide for 30 minutes to several hours. In this case, mosquitoes obtained as salts such as hydrobromide can be neutralized with sodium bicarbonate or the like to obtain the desired product.

Method F

Compounds of formula (I) wherein R ¹ is carboxy lower alkyl, amino lower alkyl or mono- or di-lower alkyl amino lower alkyl can be obtained according to method E Rou general formula

(In the formula, each symbol has the same meaning as described above.)

Compounds represented by the general formula

R ⁶ — Z (XV)

(In the formula, R ⁶ represents a carboxy lower alkyl, an amino lower alkyl or a mono- or G-lower alkylamino lower alkyl, and Z represents a yion residue.)

Can be obtained by reacting a compound represented by the following formula [hereinafter, compound (XV) and ぃぅ].

The reaction is usually carried out in an excess of compound (XV) in an inert solvent such as benzene, toluene, aceton, dimethylformamide, methylethylketone, etc., in a solvent inert to triethylamine, sodium carbonate. It proceeds from room temperature to about 10 Q'C in the presence of deoxidizing agents such as stream, potassium carbonate and sodium bicarbonate. The thus-obtained compound of the general formula (I) of the present invention can be isolated and purified by a conventional method such as a recrystallization method or a chromatography method.

Further, the compounds of the general formula (I) of the present invention include inorganic acids (hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, etc.), organic acids (fumaric acid, maleic acid, succinic acid, tartaric acid, p-toluene, etc.). Sulfonic acid) to give the above-mentioned acid addition salt. When the compound has a carboxyl group in the molecule, metal hydroxides (such as sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminum hydroxide), ammonium hydroxide, and ammonium hydroxide N

(Triethylamine, etc.) and amino acids (such as lysine and glutamine) can be treated in a conventional manner to give the corresponding salts described above.

Hereinafter, the present invention butadiene compounds Ni'ite of 5 Li Bokishige kinase-inhibiting activity, lipid peroxidation inhibiting action, Roi co preparative Lin D ₄ antagonism, of free inhibitory activity of Hisuta Mi Noyobi SRS- A Tests and their results are shown.

The control drug in the table is 6— (12—hydroxy-1,5,10—dodecadinyl) -1,2,3,5—trimethyl-1,1,4-benzoquinone (AA—86) 1) is shown.

Test example 1

5-lipoxygenase action inhibitory activity

Test

According to the method of Ochi et al. [Refer to J. Biol. Chem., Vol. 258, Vol. 57, pp. 574-575 (1988)]. The supernatant fraction of 105,000 X g of morphonuclear leukocytes was prepared, and the ability to produce 5-hydroxyhydroxysate traenoic acid (5—HETE) from arachidonic acid was measured.

An intraperitoneal injection of 110 volumes (10 ml / 100 g body weight) of a 2% casein solution into a male guinea pig weighing approximately 500 g was performed, and after 16 to 18 hours, the abdomen was opened. The cells were collected, and in the next step, two strokes were intraperitoneally washed with a saline solution containing a 10 mM phosphate buffer (pH 7.4). The obtained leachate and washing solution were collected, centrifuged at 15 O X g for 5 minutes, and 0.2% saline was added to the precipitate, and the mixture was subjected to hypotonic treatment and mixed. The red blood cells were lysed. After adding 1.6% saline to make the solution isotonic, centrifugation is carried out in the same manner, and the suspension is suspended in 5 OmM Hepes buffer (ρΗ80), followed by sonication (Branson sonifier, model 185). ). Centrifuge at 10,000 X g for 10 minutes, centrifuge the supernatant at 105,000 X g for 60 minutes, and use the resulting supernatant as the 5-riboxygenase fraction until use. -Stored frozen at 70 ° C.

Is the reaction solution 5 OmM? ris- HCl buffer (. PH7 3) during the 5 over Li _{Pokishigenaze:.} 'Er' fraction (0. 5 m protein), 3, 4 〃 M [1 - ^{1 4} C] Araki Don acid (4 0 n C i ,. mersham International), 1 m M saw Complex of ATP (Adeno Shin three-phosphate) per cent Yobi 1 m M Group Chion chloride Karushiu j, 2 m M, and the total volume of 0. 2 ml _beta dimethacrylate The test compound and the supernatant fraction dissolved in thiolsulfoxide were pre-incubated for 30 minutes with 30 minutes, and then C-arachidonic acid was added, and the mixture was subjected to rush reaction for 30 minutes for 3 minutes. The reaction was quenched by the addition of 20 carboxylic acid solution 20, and the reaction product was extracted with 1 ml of ethyl ether. Then, anhydrous sodium sulfate 0.5 was mixed and lightly centrifuged. The supernatant was transferred 0.6 ml to another test tube, after dryness, using chloroform: methanol (2: 1) was dissolved in 5 0 ^, and spot Tsu preparative silica dim plate (Whatman, LK ₅ DF) to. Plates were spotted with arachidonic acid, a standard product, staglandin B ₂ , 5- and 12-HETE as markers. Ethyl ether-petroleum ether-acetic acid (85: 15: 0.1) using a developing solvent to separate the upper layer chromatograph and Linya's analyzer (Berthoid, model LB 282) 5—HETE generation The amount was determined.

to

Obtained in 50% inhibitory concentration for 5 Li Bokishigenaze inhibitory effect of 5-Eta E T E production of the test compound (IC _5., M), The results are summarized in Table 1.

Table 1 Test compound 5-lipoxygenase inhibitory ability

Compound 3 X 1 of I Cso (M) Example 2 5 0 - ⁸

Example 3 1 compound 7~ 9 X 1 0 - ⁸

Compound 5 X 1 Example 3 3 0 - ⁸

Example 3 8 Compound 4 X 10 ' ⁸

Example 40 Compound 4 X 10 " ⁸

Compound 5 X 1 Example 5 2 0 - ⁸

Controls 3 X 10 — ^{7 As is} evident from Table 1, the compounds of the present invention show significantly superior 5-lipoxygenase action inhibitory activity in comparison with the control drug. did.

Test example 2

Lipid peroxidation prevention

Trial

The lipid peroxidation inhibitory effect of the compound of the present invention was carried out according to the method of Shimada P. Yasuda (see Biochim. Biophys. Acta, Vol. 489, pp. 1663 (1977)). Using a male rat weighing about 200 g, a liver microsome suspension was prepared in the usual manner, and this was added to 100 μl of ascorbic acid and 200 μl of ferrous sulfate. After reacting at 37 'C for 60 minutes in the presence of M, the amount of malonaldehyde produced was measured by the Thiobarbilic acid method.The test compound was added before the reaction.

.

The lipid peroxidation inhibitory effect of the test compound was determined at a ₅₀ % inhibitory concentration (IC ₅₀ , M) for malonaldehyde formation in the control group, and the results are summarized in Table 2.

Table 2 Test compounds Lipid peroxidation prevention

I Cs. (M) Compounds 1 to 3 X 107 of Example 40 Compounds 1 to 3 X 10-7 of Example 41 Compounds 1 to 3 X 10-7 of Example 4 Compound 1 of Example 45 ~ 3 X 107 Compound of Example 46 1 ~ 3 X 107-7 Compound of Example 47 ~ 3 X 107-7 Test example 3

Roi co Application Benefits E down D ₄ (excised LTDJ掊抗acting male guinea pig DOO picture intestine, creating the conventional method Nyori Echoshirube. Specimens 1 0 was bubbled air at a bath temperature of 3 7 ° C 0.75 g of food was suspended in a Magnus tube containing ml of nutrient solution and fixed at the lower end of the target, and the upper end was isotonic with a transducer (CP—2U—3 3, Midori Precision) and its contraction was recorded isometrically on a recorder (R-14, Rika Denki) 5 X 10-0 ^{1. According to} M LTD 4 (PAESBL GmbH ί Co) Mencho contractile response was examined anti LTD ₄ action of stable after test solution pretreatment time of the test solution and 2 minutes, in the presence of test fluid _{LTD 4 5 X 1 0 -.} . 10 M Nyoru . the extent of the contraction was compared with shrinkage during the test liquid without addition Nao, 5 X 1 is a nutrient solution 0 - ⁷ M § tropine pressurized Eta.

Result

LTD. Antagonism of 50% inhibitory concentration (IC _5., G Roh ml) shown in Table Washi, in Table 3.

Table 3

L T D 4 antagonism

IC _5. (G / ml) Compound of Example 3 1 3. 1 X 1 0 - 7 Test Example 4 Release of histamine and SRS-A from sensitized guinea pig lung.

Dish

Male guinea pigs were sensitized by intraperitoneally or subcutaneously administering 10% ovalbumin 10% ovalbumin. Three weeks later, the animals were sacrificed by exsanguination, and the blood was removed by diversion of the lungs with a tidal solution of 5 through the pulmonary vein. The trachea and large bronchi were removed from the removed lung and minced. Add 4.5 ml of Tide solution and 0.5 test solution to 1 g of lung tissue, hold for 3 minutes at 37, and add 0.05% 1% egg white albumin. It was heated and kept at 37'C for 5 minutes. Thereafter, the reaction solution was centrifuged, 0.1 N of 4 N was added to the supernatant of 1 to remove proteins, and histamine was quantified by the fluorescence method of Shore et al. SRS - A in guinea pig preparative image intestine in the presence of the remaining from the supernatant 1 0- ⁶ M main pyramidal Noyobi 5 X 1 0- ⁷ M sulfuric § preparative Ropin hydrate (Wako Pure Chemical) Quantified.

Result

The activity of inhibiting the release of histamine and SRS-A was expressed in percentage and is shown in Table 4.

Table 4 Dose (M) Hisosemin free SBS-A release inhibitory activity) Inhibitory activity (%) Compound of Example 31 1 20.0 0.03.8

1 0 0 4 7.3 1 0 0 4 5.8 1 0 0 **

**: <0.01 In addition, the butadiene compound of the present invention and salts thereof are remarkable for humans and other animals such as horses, horsetails, pigs, dogs, mice, rats, guinea pigs, and the like. - having Li Pokishigenaze-inhibiting activity, lipid peroxide inhibiting action, Russia I co Application Benefits E down D ₄ antagonism, the free activity of Hisuta Mi Noyobi SRS- a.

The butadiene compounds Oyobi acute toxicity values of Example 3 1 of a compound of a salt thereof Ari low toxicity, other and Eba invention of the present invention (LD _{5 0,} dd-strain male Mausu) is a route of administration> 1 , 0.000 mg Z kg, and> 300 nig / kg by intraperitoneal administration.

As has been clarified above, the butadine compound of the present invention and its salt can be used in animals such as horses, horses, horses, pigs, dogs, mice, rats, guinea pigs and the like. Bronchial asthma, allergic diseases (such as allergic rhinitis), immune diseases (such as autoimmune deficiency and infectious diseases), inflammatory diseases (such as rheumatoid arthritis and ankylosing spondylitis), psoriasis, and cerebrovascular disorders It is useful as a therapeutic agent for various diseases such as ischemic heart disease and hematopoiesis.

The dosage of the butadiene compound of the present invention and its salt varies depending on the disease, the seriousness of the patient, the tolerability to the drug, etc., but is usually 5 to 50 Om / day for an adult. It should be administered in one or divided doses. Upon administration, any condition suitable for the administration route can be adopted.

The butadiene compound and its salt of the present invention can be prepared for administration using any conventional formulation method. Therefore, the present invention also covers a pharmaceutical composition having at least one butadiene compound or a salt thereof. Such a composition can be placed anywhere It is prepared by conventional means using pharmaceutically acceptable additives such as essential pharmaceutical carriers and excipients.

When the composition is a preparation for administration, it is desirable that the preparation be provided in a form suitable for absorption from the digestive tract. Tablets and capsules for parenteral administration are presented in unit dosage form, for example, binders, such as syrup, arabia gum, gelatin, sorbite, trakant, polyvinylpyrrolidone, etc .; , Tobacco lactose, corn starch, calcium phosphate, sorbent, glycine, etc .; lubricants, magazine, talc, magnesium stearate, talc, polyethylene glycol, silica, etc .; disintegrant Or, for example, potato starch or the like; or an acceptable lubricant, for example, common excipients such as sodium laurylsulfate. Tablets may be coated in a manner well known in the art. Transdermal liquid preparations may be aqueous or oily suspensions, solutions, syrups, elixirs, etc., and may be added to water or other suitable vehicle before use. It may be a dry product to be redissolved. These liquid preparations are commonly used additives, such as suspending agents, such as sorbitol syrup, methylcellulose, glucos / sugar syrup, gelatin, and hydroxy. Non-aqueous vehicles, such as shamtyl cellulose, carboxymethyl cellulose, aluminum stearate gel, hydrogenated edible fats, etc .; emulsifiers, for example lecithin, sorbitan monooleate, arabia gum; , Fractionated coconut oil, oily ester, propylene glycol, ethyl alcohol, etc .; preservatives, tatoba p-methyl hydroxybenzoate, p-propyl hydroxybenzoate, You may have sorbic acid.

When preparing an injection for ti, a pH adjuster, buffer, stabilizer, preservative, solubilizing agent, etc. are added to the butadiene compound of the present invention or a salt thereof as needed, and subcutaneously according to a conventional method Intramuscular or intravenous injection.

Hereinafter, the present invention will be described specifically with reference to examples, but the present invention is not limited to these examples.

Example 1

Dissolve bistrimethylsilylamine 27 in tetrahydrofuran 60, cool it to 50 and 30 and add 15% n-butyllithium in 15% n-hexane solution to this solution. ^ Is dropped in about 15 minutes. , 7.4 g of Wittig reagent prepared with 4-chloromethylpyridine hydrochloride and triphenylphosphine was suspended in 60 ^ ^ Cool down. The bistrimethylsilylamine lithium salt solution prepared above is added dropwise to the cooled suspension containing the Zittig reagent over about 2 hours. In this case, the reaction solution was kept at-50 'C 30' C. After completion of the dropwise addition, the reaction solution is warmed to room temperature and stirred for about 0.5 hour. To the reaction mixture is added 3.9 g of α-methyl-14-methoxycinnamaldehyde, and the mixture is stirred at 40 for 24 hours. The reaction so far is performed under a nitrogen atmosphere. After completion of the reaction, the insoluble precipitate is removed by filtration, and the filtrate is concentrated under reduced pressure. The residue was subjected to silica gel chromatography, and purified using chloroform as an eluent to give 4— [4— (4—methoxyphenyl) -13—methyl-1,3, butadienyl] pyri. 0.8 g of the cis form of gin was obtained in the next step, and 1.2 g of the trans form was obtained as an oil. Can be The trans form is crystallized as a hydrochloride salt in 25% ethanol-hydrochloride, and recrystallized from medanoluyl soprovir polyester to give 4 — [(Ε, Ε) -4 -(4'-Methoxyphenyl) -3- (methyl-1,3, butadienyl) pyridin 'hydrochloride • 1/2 hydrate 1.1 g is obtained. Melting point 1 79 〜 1 8 1

Example 2

The cis form of 4- [4- (4-methoxyphenyl) -3- (methyl-1,3-butadienyl) pyridine obtained in Example 1 was converted to the hydrochloride salt with 25% ethanol-hydrochloride. When recrystallized from methanol isopropyl alcohol, it was found that 4 ([(Ζ, Ε)-4-(4-methoxyphenyl)-3-methyl-1, 3-butagenyl) viridine 'hydrochloride 0 .7 g are obtained.

The following compounds are obtained by performing the same processing as in Examples 1 and 2 above.

Example 3

2 - _{[(E S E) - 4 -} (4 over main Tokishifeniru) Single 3 - methyl one 1, 3 - Pig Jeniru] Pi lysine hydrochloride, mp 1 5 8-1 6 0

Example 4

4- (B, E) -4- (2-Methoxyphenyl) -1-3-Methyl-1,3-buta-genyl pyridine · hydrochloride · 4/5 hydrate, melting point 199- 2 0 2

Example 5

2 — [(E, E)-4-(2-methoxyphenyl) 13-methyl 1, 3-butadienyl] pyridine hydrochloride, mp 180-1 8 2 'C

Example 6

4 — [(Ε, Ε)-4-(3, 4 — dimethoxyphenyl)-3 — methyl-1,3-butadidinyl] pyridin.Hydrochloride, mp 2 16 to 2 18 ' C

Example 7

2 — [(Ε, Β)-4-(3, 4-dimethoxyphenyl) 1-3-methyl-1,3-butadienyl] pyridin hydrochloride, melting point 18 1 -18 2

Example 8

4-[(Β, Β)-4-(2, 4 —dimethoxyphenyl) -3- 3 -methyl-1,3-butadienyl] pyridin * hydrochloride, mp 2 15 to 2 17

Example 9

2-[(Ε, Β)-4-(2, 4 —dimethoxyphenyl) 1 3 — methyl-1,3 —butagenyl] pyridin hydrochloride, melting point 17 1 〜: L 7 2 ' C

Example 10

4-C (Β, Ε)-4-(3, 4, 5 — trimethoxyphenyl) — 3 —methyl-1,3 —butagenyl) viridin 'hydrochloride, melting point 229- 2 3 0 'C (decomposition)

Example 1 1

2-C (Β, Β)-4-(3, 4, 5 —trimethoxyphenyl) -3- 3 -methyl 1,3 -butagenyl) pyridin 'hydrochloride, melting point 19 7 ~ 1 9 9 'C (decomposition) Example 1 2

4 — ((E, E)-4-(3,5-dibromo-4 — methoxyphenyl)-3 — methyl_1,3 — butagenyl) pyridine 'hydrochloride, mp 21 1 to 21 3 (Disassembly)

Example 13

2 — [(Β, Ε)-4-(3,5-dibromo-1- 4-methoxyethoxy) -3 -methyl-1,3-butadienyl] pyridine 'hydrochloride, mp 197-199 ° C (decomposition)

Example 14

4-[(E, E)-4-(4 -Methoxy-1,3,5-dimethylthiophenyl) 13 -Methyl-1,3 -butagenyl] Viridine 'hydrochloride, melting point 2 24 to 2 25 (Decomposition)

Example 15

2 — [(Ε, Ε) -4-(4-methoxy-1,3,5-dimethylthiophenyl) -3 —methyl-1,3 —butagenyl] pyridine 'hydrochloride, mp 195-198 'C (decomposition)

Example 16

4-[(Β, Ε)-4-(4 -Methoxy-1 3 -methylphenyl) 13 -Methyl-1, 3 -Butajenyl] pyridine 'hydrochloride, melting point 2 13 to 2 15 (Disassembly)

Example 1

2-[(Ε, Ε)-4-(4 -Methoxy-1 3 -methylphenyl)-3 -Methyl-1, 3 -Butajenyl] pyridine * hydrochloride, melting point 177-17-178 8 (Disassembly)

Example 18 2-[(Β, Ε) -4- (4-Methoxy-1,3,5-dimethyldiphenyl) -1-3-Methyl-1,3-butadidinyl] -14-oxo-13 3-Quinazoline hydrochloride, Melting point 250 to 25 2 'C (decomposition) Example 19

Reaction of 4-chloromethylviridine hydrochloride with dimethyl reagent prepared with triphenylphosphine and or-methyl-3, 4-dimethoxycinnamaldehyde as in Example 1. The residue obtained as a mixture was crystallized as a hydrochloride salt in 25% ethanol hydrochloride, and further recrystallized from methanol-isopropylate to give 4 — [(3,4 dimethylphenyl) 13 — Methyl-1,3-butadienyl] viridin 'hydrochloride is obtained. Melting point 201-203

Example 20

Dissolve 30 m of bistrimethylsilylamine in 50 mi of tetrahydrofuran, cool to 50'C 30'C, and add n-to 15% n-butyrridium in this solution. Twenty-five mi of a hexane solution is added dropwise over about 15 minutes to prepare bistrimethylsilylaminolithium salt. 4—Benzyloxy 1,3,5—Disobrovir Benzyl chloride and triphenylphosphine 15 g of the prepared reagent are suspended in 15 Om of tetrahydrofuran. Turn cloudy and cool to 150-130. The bistrimethylsilylamine lithium salt solution prepared above is added dropwise to the Wittig reagent over about 2 hours. The reaction solution was kept at −50 ′ C 30 ′ C. After completion of the dropwise addition, the reaction solution was warmed to room temperature, stirred for about 0.5 hour, and then 3.5 g of 3- (4-vinyl) -acrylaldehyde was added. Stir at 24 ° C for 24 hours. The operations so far were performed in nitrogen gas. After completion of the reaction, the insoluble precipitate was removed by filtration, concentrated under reduced pressure, and the residue was purified by silica gel to give 4-[4-(4-benzyloxy-1,3,5-diisopropyl phenyl). 1,3-butadienyl] pyridine 5. lg is obtained as an oil. The oil was converted to the hydrochloride salt with 25% sodium propyl alcohol and recrystallized to give 4-((Ε, Ε) -4- (4-benzyloxy-1,3,5-di) as yellow crystals. Sopropyl phenyl) 1,3-butadienyl] pyridine hydrochloride (2.2 g) is obtained. Melting point: 236-238'C (decomposition) By performing the same treatment as in Example 20, the following compound can be obtained.

Example 2 1

4-[(E, E)-4-(4 -benzyloxy 3 5-dimethylphenyl)-1, 3-butagenyl] Viridine hydrochloride · monohydrate, mp 197-198 ' C

Example 22

4-[(Ε, Β)-4-(4 -benzyloxy 1 23, 5 -trimethyltylphenyl) 1, 3 -butagenyl] pyridine, mp 13 6 -1 3 7

Example 23

4 — ((Ε, Ε) — 4 — (4—Methoxy 1> 3,5,6—Tetramethylphenyl) -1,3—Butajenyl] pyridine, mp 130-131

Example 2 4

2 — [(Ε, Ε)-4-(3, 4 — dimethyoki obtained in Example 7 1-, 3-methyl-1,3-butadienyl] pyridine

2.0 g and 20 m of methyl chloride were stirred at room temperature for 10 hours, and after the reaction was completed, excess methyl chloride was removed under reduced pressure, and the residue was collected in methanol. When crystallized from Sopro-Piretel, 2

— (3,4—Dimethoxyphenyl) 1-3—Methyl-1,3—butagenyl) —1—Methylpyridinidine Amount 2.2 g is obtained. Melting point 25 1 ~ 25 2 'C (decomposition)

Example 2 5

2 — [(Ε, Ε)-(4-methoxy-3,

5 -Dimethylphenyl) -3 -Methyl-1,3, butadienyl] Dissolve 2.7 g of pyridine in 15 mi of dichloromethane and cool with ice. In the next step, a solution of 4.8 g of boron tribromide in dichloromethane with stirring

Add 2, stir under ice cooling for 1 hour, and drop about 10 m of methanol. After completion of the reaction, the solvent was decompressed and distilled off, and the obtained orange residue was recrystallized from methanol to give 2 — [(Ε, Ε) —4— (4—hydroxyl-3 as orange crystals. 1,5-Dimethylphenyl) -3- (methyl-1,3-butadienyl) pyridine'hydrobromide monohydrate 1.4 g is obtained. Melting point 2 2 4 to 2 2 7 (decomposition)

The following compound is obtained by performing the same processing as in Example 25 described above.

Example 26

4-[(Ε, Ε) — 4 — (2 — hydroxyphenyl) 1-3 — methyl — 1, 3 — butadenyl] pyridine · hydrobromide, mp 2 3 3 to 2 3 4 'C

Example 2 7 2 — ((E, B)-4-(2 — hydroxyphenyl) 1 3 — methyl 1, 3 — butadienyl] pyridin 'hydrobromide · 1/2 hydrate Material, melting point 206-208

Example 2 8

4-[) 1 4-(4-hydroxyphenyl)-3-methyl-1, 3-butagenyl] pyridin hydrobromide, melting point 219-221. C

Example 2 9-

2 — [((Ε, Ε)) — 4 — (4 — doxydoxyphenyl) -1 3 —methyl-1,3 —butagenyl] pyridin hydrobromide, melting point 2 29 to 2 3 0

Example 30

4-([Ε, Ε) —4— (3,4—dihydroxyphenyl) -3-methyl-1,3-butadienyl] pyridinine'hydrobromide, mp 24 9 ~ 250 ° C (decomposition)

Example 3 1

2 — [(Ε, Β)-4-(3, 4 — dihydroxyphenyl) — 3-methyl-1,3-butadienyl] pyridin hydrobromide, mp 2 27 ~ 2 2 9

Example 3 2

4-((Ε, Ε)-4-(3, 4, 5 — trihydroxyphenyl) — 3 —methyl-1,3 —butagenyl) pyridine / hydrobromide 1/4 hydrate, melting point 2 45 to 2 4 6 'C (decomposition)

Example 3 3

4-[(Β, Ε)-4-(4-Hydroxy 3, 5- 1-, 3-Methyl-1,3-butadienyl] pyridine.hydrobromide, mp 2338-239 (decomposition)

Example 3 4

4-[(Ε, Ε) —4— (3,5—dibromo-14-hydroxyphenyl) -13—methyl_1,3-butadienyl] pyridine'hydrobromide, mp 233- 2 3 4 (Disassembly)

Example 3 5

2 — [(Ε, Ε) — 4- (3,5-dibromo-1-hydroxyphenyl) -1-3-methyl-1-, 3-butadienyl] Biridine 'hydrobromide, melting point 2 3 3 ~ 2 3 6 (disassembly)

Example 3 6

4 — [(Ε, Ε)-4 ~ (4 —hydroxy-3 —methylphenyl) -3 —methyl-1,3, butadienyl] viridin · hydrobromide, melting point 2 28-2 2 9 'C (decomposition)

Example 3 7

2 — [(Ε, Ε)-4-(4 —hydroxy 3 —methylphenyl) -3 —methyl-1-, 3-butadienyl] pyridine 'hydrobromide, mp 2 4 2 to 2 4 4 (Decomposition)

Example 3 8

2 — [(E, E)-A-(4 — hydroxy 3,5 — dimethyl phenyl) 1 3 — methyl 1, 3 — butagenyl] quinoline 'hydrobromide · 2/3 water Example 3 9 (decomposition)

2 — [(Ε, Ε)-4-(4 —hydroxy 3> 5 —dimethyl phenyl) 1 3 —methyl 1, 3 —butagenyl] 1 4 1 oxy -3H-quinazoline hydrobromide, melting point 2887-2889 (decomposition)

Example 40

2 — [(Ε, Ε) —4— (4—hydroxy-1,2,3,5—trimethyltylphenyl) -1,3-butadienyl] pyridine '2/3 hydrate, melting point 16 8 to 1 7 0

Example 4 1

3 — [(Ε, Ε) -4-(4-hydroxy-1,2,3,5 —trimethylfuryl) 1-1,3-butadienyl] pyridine * hydrobromide, mp 2700 ~ 2 7 3 "C

Example 4 2

4-[(Ε, Ε)-4-(4-hydroxy-1,2,3,5 -trimethyltylphenyl) 1,3 -butagenyl] Biridine hydrobromide, melting point 2400 ~ 2 4 3 * C

Example 4 3

4 I ((Ε, Ε)) — 4 — (4 — Hydroxy 3, 5 — Dimethyl phenyl) -1,3 — Buta genyl] Viridin hydrobromide

1/3 hydrate, melting point 2 2 1 to 2 2 3

Example 4 4

4 I ((Ε, Β)-4-(4-Hydroxy-1,3,5-Gisopropizolefenizole) -1,3 -Butajenyl] pyridine hydrobromide, mp 267- 2 6 8 'C (decomposition)

Example 4 5

3 — [(Ε, Ε)-4-(4 — Hydroxy 3, 5 — Diisopropylpropenyl)-1> 3 —Butajenyl] pyridin / hydrogen bromide Acid salt, melting point 277-279 (decomposition)

Example 4 6

2 — [(E, E)-4-(4 — Hidden mouth 3,5 — di-so-propyl pyridinyl) 1, 3 — butadenyl] Pyridinine 'hydrobromide, mp 235-2 3 8 'C (decomposition)

Example 4 7

4-[(Ε, Β)-4-(3 -tert-butyl 1-4 -hydroxy 5 -methylphenyl) 1, 3 -buta-genyl] pyridinine 'hydrobromide, melting point 2 7 5 to 2 7 7 'C (decomposition)

Example 4 8

3 — [(Β, Ε)-4-(2 — Hydroxy 1 3 5 —Dimethyl phenyl) 1, 3 —Buta genyl] Viridin hydrobromide, mp 23 6 to 2 3 7 (Decomposition)

Example 4 9

4-[(Β, Ε)-4-(4 -hydroxyl 23, 5, 6-tetramethylphenyl) 1, 3-butagenyl] bilidine hydrochloride, melting point 24 3 〜 2 4 7 t (disassembly)

Example 5 0

3 — [(Ε, Ε) — 4 — (4 —hydroxy 2,3,5,6 tramethyltylphenyl) 1,3 —buta-genyl] Viridine hydrochloride, melting point 2556-2 6 0 'C (decomposition)

Example 5 1

2 — [(Ε, Ε) — 4 — (4 —hydroxy-1,2,3,5,6 ラ tramethylphenyl) 1, 3 —butagenyl] pyridine hydrochloride, melting point 260 ~ 2 6 1 (decomposition) Example 5 2

2-[(E, E)-4-(3, 4 -dihydroxyphenyl) -3-methyl-1,3-butagenyl] quinoline 'hydrobromide, melting point 245-2 4 6 'C (decomposition)

Example 5 3

Example 2 2 — [(Ε, Β) -4- (2-hydroxyphenyl) -3- (methyl-1- 1> 3—butagenyl) obtained in 5) Viridin 'hydrobromide 1,6 g Is dissolved in a mixed solvent of dimethyl sulfoxide (2 m) and tetrahydrofuran (20 m), and thereto is added 1.4 g of finely ground calcium carbonate. While stirring at 40 to 50 ° C., 1.8 g of α-bromopropionic acid ethyl ester is added to the mixture, and the mixture is stirred under reflux for 48 hours. After the completion of the reaction, the mixture is returned to room temperature, the insoluble matter is removed by filtration, and the filtrate is concentrated under reduced pressure. The obtained residue is subjected to silica gel chromatography, and purified with chloroform (30: 1) as a developing solvent. Dissolve 1.9 g of the obtained pale yellow oil in methanol, and add 2.5 mi of a 4N sodium hydroxide solution thereto. Stir at room temperature for 2 hours, then concentrate under reduced pressure, and add water and 1N hydrochloric acid to the remaining solution to adjust the pH of the solution to about 4. The precipitated crystals were collected by filtration and dried, and 1.5 g of a yellow powder obtained was recrystallized from methanol to give 2 — [(—, 2) -4-4- (2— ( 1-Carboxyethoxy) phenyl) 1-3-methyl-1,3-butadienyl] pyridine is obtained. Melting point 1 8 3 to 1 8 4

Example 5 4

4-((E, E) —4— (2—hydroxy) obtained in Example 26 Disenyl) 3- (methyl-1,3-butadienyl) vilidine 'hydrobromide (2.0 g) was dissolved in a mixed solution of dimethyl sulfoxide (3 m) and acetate (30 m). 2.6 g of finely ground carbonated carbonate is added to this. At room temperature, 2.7 g of dimethylaminoethyl chloride ¹ J hydrochloride was added, and the mixture was stirred at reflux for 48 hours. After completion of the reaction, the insolubles are removed by filtration, the filtrate is concentrated under reduced pressure, and water and ethyl acetate are added for extraction. After the organic layer is dried over magnesium sulfate, the solvent is distilled off to obtain a brown oil. This oily substance is dissolved in isopropanol alcohol, and then, isopropanol alcohol hydrochloride is added, followed by addition of isopropyl ether, and the resulting sediment is filtered off to give an ocher color. 1.5 g of powder are obtained. When recrystallized from ethanol-isoprovir ether, it was obtained as ocher crystalline powder 41 [(E, E) -3-methyl-1 4- (2— (2-dimethylmethylaminoethoxy) phenyl) 1-1, 3 —Butajenyl] 0.8 g of viridin 'dihydrochloride is obtained. Melting point 2 15-2 18 'C (decomposition)

The following compounds are obtained by performing the same treatment as in Examples 53 to 5 described above.

Example 5 5

4 — [(E, E) — 4 ー (2 — (1 — carboxy phenyl) phenyl) 1 _ 3 _ methyl 1, 3 — butagenyl] pyridine, melting point 2 1 1 to 2 13 C (decomposition)

Example 5 6

2 — [(E, E)-4-(4-(1 -carboxyl phenyl) phenyl) 1-3-methyl 1, 3-butagenyl] viridin, melting point 16 5-: L 66 'C Example 5 7

2 — [(Ε, Ε) — 3 — Methyl 4- (2- (2 — dimethylamino) phenyl)-1, 3 — Butagenyl] pyridin 'disalt Acid salt, melting point 210-211 ° C (decomposition)

Example 5 8

2-((Ε, Ε) —3—Methyl-1-4- (4— (2-dimethylaminophenyl) phenyl) 1-1,3—Polygenyl) Pyridine

Dihydrochloride, melting point 1997-200 'C

Next, one of the butadiene compounds of the present invention, 2 — [(Ε, Ε) -4- (3,4—dihydroxyphenyl) 13—methyl-1> 3> -butagenyl) pyridine · Formulation examples using hydrobromide (the compound of Example 31) as an active ingredient are shown.

Example 5 9 capsules

20 g of the compound of Example 31

Microcrystalline Cellulose 6 5 g

Corn starch 20 g

Lactose 2 2 g

Polyvinylpyrrolidone 3 g Total 1 30 g

After granulating the above ingredients according to the usual method, gelatin hard capsule

1,000 capsules were filled. One capsule contains 20 mg of the compound of Example 31.

Example 6 0

50 g of the compound of Example 31 Microcrystalline cell α-size 400 g corn starch 550 g Total amount 1,000 g The compound of Example 31 was dissolved in acetone, and this was added to microcrystalline cellulose in the next step. After adsorption, it was dried. This was mixed with corn starch, and a 20-fold powder of the compound of Example 31 was prepared as a powder in a conventional manner.

Example 6 1 JEM

Example 3 Compound of 1 10 g Tumoroko starch 10 g Lactose 20 g Carboxymethyl cellulose calcium 10 g Microcrystalline cellulose 35 g Polyvinyl viridone 5 g Talc 10 g Total amount 100 g Example 31 The compound of Example 1 was dissolved in acetone, which was adsorbed to microcrystalline cellulose in the next step, and then dried. This was mixed with corn starch, lactose, and carboxymethyl cellulose calcium, followed by adding an aqueous solution of polyvinylpyrrolidone as a binder and granulating according to a conventional method. This was mixed with talc as a lubricant, and then tableted into 100 tablets. One tablet contains 10 mg of the compound of Example 31. Example 6 2 Injection

Example 3 Compound of 1 10 g Solubilizer Nikkol HC0-60 (Nikko Chemicals product name) 37 g Sesame oil 2 g Sodium chloride 9 g Propylene glycol 40 g Phosphoric acid Buffer (0.1 M> PH 6.0) 100 g Distilled water Total volume 1, 00 g Nikkol HCO-60. Compound of Example 31. Sesame oil and half of propylene glycol are mixed. The mixture is heated and dissolved at about 80 ° C, and heated to about 80 ° C with distilled water in which a phosphate buffer solution and sodium chloride and propylene glycol have been previously dissolved. A total of 1,000 aqueous solutions were used. This aqueous solution was dispensed into 2 l samples, sealed, and then sterilized by heating.

One tube contains the compound 2 O nig of Example 31.

According to the present invention, a novel butadiene compound useful as a medicine is provided. As is evident from the results of the above tests, the butadine compound of the present invention can markedly inhibit the action of 5-lipoxygenase, and thus, is formed by the action of 5-lipoxygenase. It is possible to effectively suppress the production of rococo regens, such as LTC ₄ and LTD 4, which are allergy onset factors. In addition, the butadiene compound of the present invention has an antiallergic action, an antihistamine action, a lipid peroxidation preventing action, and a blood cell aggregation inhibiting action.

Claims

The scope of the claims

1. ー general formula

(Wherein, R ¹ is hydrogen, lower alkyl, carboxy lower alkyl, amino lower alkyl, mono or di-lower alkyl amino lower alkyl, aralkyl, and η 偭 R ² is halogen, lower alkyl, Lower alkoxy, hydroxyl group, R ³ is hydrogen, lower alkyl, Het, pyridyl, N-lower alkylpyridine, quinolyl, 4-oxo 3 H-quinazolyl, n is an integer of 0 or 1 to 4 shown. However, when the II indicates螯数of. 2 to 4, n pieces of R ² is Yoi be the same or different Nutty.)

A butadiene compound represented by the formula: or a salt thereof.

2. 4 — [(E, E) —4— (4—Methoxyphenyl) -3—methyl-1,3-butadienyl] pyridine

4-[(Ζ, Ε)-4-(4 -Methoxyphenyl)-3 -methyl-1,3 -butagenyl]

2-C (Ε, Β)-4-(4 -Methoxyphenyl) -3 -Methyl-1,3 -Butajenyl] pyridine

4 — [(Ε, Ε)-4-(2 — methoxyphenyl) 1 3 — methyl — 1, 3 — butadenyl] bilidine

2 — [(Ε, Ε) -4-(2-Methoxyphenyl) 1 3 —Methyl — 1,3 —Butajenyl] Biridine

4 I ((Ε, Ε)-4-(3, 4 —dimethoxyphenyl)-3 — 1-, 3-methylbutadienyl) pyridin

2 — [(Β, Ε)-4-(3, 4 — dimethoxyphenyl) 1 3 — methyl 1> 3 — butadienyl]

4-C (Ε.Ε)-4-(2, 4 —dimethoxyphenyl) 1 3 — methyl 1, 3 —butagenyl) pyridin

2 — [(Ε ₅ Ε)-4-(2,4-dimethoxyphenyl) 1 3 — methyl 1, 3 — butagenyl)

4-ί (Ε, Ε)-4-(3, 4, 5 — trimethoxyphenyl) — 3 — methyl 1, 3 — butagenyl)

2 — [(Ε, Ε) — 4 — (3,4,5—trimethoxyphenyl) — 3—methyl-1,3—butagenyl)

4 — [(Ε, Ε)-4-(3, 5 — dibromo 4 — methoxyphenyl) 1 3 — methyl 1, 3 — butagenyl)

2-[(Ε, Ε)-4-(3, 5-dibromo 1-4-methoxyphenyl) 1-3-methyl 1, 3-butagenyl] viridin

4 1 [(Ε, Ε)-4-(4 —Methoxy 3, 5 —Dimethylphenyl) 1 3 —Methyl 1> 3 — Butadienyl] Pyridine

2-[(Ε, Ε)-4-(4 —Methoxy 3, 5 —Dimethylphenyl) 1 3 —Methyl 1, 3 —But genenyl] Pyridine

4-C (Ε, Ε)-4-(4 -Methoxy 3 —Methylphenyl) — 3 —Methyl 1, 3 —But genenyl]

2 — [(Ε, Ε)-4-(4 -methyl 3 -methylphenyl)-3 -methyl 1, 3 -butagenyl]

2 — [(Ε, Ε)-4-(4 — methoxy 3, 5 — dimethylphenyl) 1 3 — methyl 1, 3 — butagenyl) 1-4 oxo 3 H—Quinazoline

4 — [(3,4 — dimethoxyphenyl) 1 3 — methyl 1, 3-butadienyl] pyridine

4-[(Ε, Β)-4-(4-benzyloxy 3> 5-diisopropylpropylphenyl) 1, 3-butadenyl] pyridine

4-[(Ε, Ε)-4-(4 -benzyloxy 3,5 -dimethylphenyl) 1, 3 -butagenyl] pyridine

4 — [(Ε, Ε) — 4 — (4 — benzyloxy 1, 2, 3, 5 — trimethyl phenyl) 1, 3 — butadenyl] pyridine

4— [(Ε, Ε) — 4— (4—Methoxy 2, 3, 5, 6—tetramethyl phenyl) -1,3—butagenyl) viridine

2 — [(Ε, Ε)-4-(3, 4 — dimethoxyphenyl) 1 3 — methyl-1,3-butadienyl] 1 1 — methylbilidinidine

2 — [(Ε, Ε)-4-(4 -hydroxy-1,3,5 -dimethylphenyl) 1 3 -methyl 1,3, butadenyl]

4 — [(Ε, Ε)-4-(2 — hydroxyphenyl)-3 — methyl 1, 3 — butadenyl] bilidine

2-[(Β, Ε)-4-(2-hydroxyphenyl)-3-methyl 1,3-butadienyl] pyridin

4-((Ε, Ε) -4- (4-hydroxyphenyl) 1-3-methyl-1,3-butadienyl) pyridine

2 — Γ (Ε, Ε)-4-(4 — hydroxyphenyl) 1 3 — methyl 1, 3 — butagenizole] pyridine

4 — [(Ε, Β)-4-(3, 4 —dihydroxyphenyl) — 3 1-, 3-methylbutadienyl) pyridin

2 — [(Ε, Ε)-4-(3, 4 — dihydroxyphenyl) 1-3-methyl 1, 3 — Buta-genyl] pyridin

4-[(Β, Ε)-4-(3, 4, 5 — trihydroxyphenyl) 1 3 — methyl 1, 3 — butagenyl) pyridin

4 — [(Ε, Ε)-4-(4 — hydroxy 3, 5 — dimethyl phenyl) 1 3 — methyl 1, 3 — butagenyl)

4 — [(Ε, Ε)-4-(3 5 — dibromone 4 — hydroxyphenyl) 1 3 — methizole 1 3 — pig genenyl]

2 — [(Ε, Ε)-4-(3 5 —dibromo-4 —hydroxyphenyl) — 3 —methyl-1 3 -butadienyl] pyridin

4-((Ε, Ε)-4-(4 Hydroxy 3 —methylphenyl) — 3 —Methyl 1, 3 —But Jenyl] Pyridine

2-[(Ε, Ε)-4-(4 -Hydroxy-1- 3 -methylphenyl)-3 -Methyl-1, 3-Butagenyl]

2 — [(Ε, Β)-4-(4-hydroxy-1,3,5—dimethylphenyl) 1-3—methyl1,3, buta-genyl] quinoline

2 — [(Ε, Ε)-4-(4 — Hydroxy 1, 5 — Dimethyl phenyl) 1 3 — Methyl 1, 3 — Butagenyl] 1 4 — Oxy — 3 Η— Quinazoline

2 — (: (Ε, Ε) — 4 — (4 — Hydroxy 2> 3, 5 — Trimethyl phenyl) 1, 3 — Butagenyl) pyridin

3 — [(Ε, Ε) — 4 — (4 — Hydroxy 2, 3, 5 — Trimethyl phenyl) 1, 3 — Buta genyl] pyridin

4 — [(Ε, Ε) — 4 — (4 — Hydroxy 2> 3, 5 — Trim Cisolephenisole)-1, 3-butadienyl] pyridin

4 ー [(Ε, Ε) — 4 — (4 — Hydroxy 3, 5 —dimethyl phenyl) — 1,3-butadienyl] pyridine

4― [(Ε, Ε) ー 4 — (4 — Hydroxy 3, 5 —Jisop Pirphenyl) — 1, 3 —But Jenil]

3-[(Ε, Ε) -4- (4—hydroxy-3,5—diisopropylpropylphenyl) —1,3—butadienyl] viridine

2 ー [(Β, Ε)-4-(4 — Hydroxyl 3, 5 — Gisopropylphenyl) ー 1, 3 — Pork genil] Viridin

4 ー [(Ε, Ε)--(3 -tert-butyl-4- 4-hydroxy 5 -methylphenyl) 1 1, 3 -butagenyl] viridine

3 ― [(Β, Ε)-4-(2 — hydroxy 3, 5 —dimethylphenyl) — 1, 3 —butagenyl] viridin

4 ー [(Ε, Β)--(4 — Hydroxy 1, 2, 3, 5, 6 — Tetramethyl phenyl) 1, 3 — Buta genyl] pyridine

3 ー [(Ε, Β)--(4 — Hydroxy-1,2,3,5,6 —Tetramethyl phenyl) 1, 3 —But genenyl] Bilidine

2-C (Ε, Ε)--(4 — hydroxy 2,3,5,6 —tetramethylphenyl) -1,3 —butadienyl] pyridine

2 ー [(Β, Ε)-4-(3, 4 —dihydroxyphenyl) 1 3 —methyl 1> 3 —butagenyl] quinoline

2 ー [(Β, Β)--(2-(1 -carboxyl) phenyl)-3 -methyl 1,3 -butagenyl]

4 ― [(Β, Β) — 3 —Methyl 1 4 — (2-(2 —Dimethylaminocetenyl) phenyl) 1, 3 —Butajenyl] Viridin 4-[(E, E)-4-(2 — (1 -carboxyethoxy) phenyl) 1-3-methyl 1, 3-butadienyl] pyridine

2 — [(E, E)-4-(4-(1 -carboxyethoxy) phenyl) 1-3-methyl 1, 3-butadienyl] pyridine

2-[(£, £)-3-methyl 4--(2-(2-dimethylaminoethoxy) phenyl) 1, 3-butadienyl] pyridine

Claim 1 which is selected from 2 — [(Ε, —) — 3—methyl-1- 4- (4- (2-dimethylaminoethoxy) phenyl) 1-1,3—buta-genyl] pyridine Or a salt thereof.

3. A pharmaceutical composition comprising the compound according to claim 1 or 2 or a salt thereof as an active ingredient.